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The Journal of Neuroscience, April 2, 2008, 28(14):3567-3576; doi:10.1523/JNEUROSCI.4679-07.2008

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Neurobiology of Disease
Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures

Cuie Qiu,¹ Thomas Zeyda,² Brian Johnson,¹ Ute Hochgeschwender,³ Luis de Lecea,⁴ and Melanie K. Tallent¹

¹Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19348, ²John A. Burns School of Medicine, Honolulu, Hawaii 96813, ³Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, and ⁴Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California 94304

Correspondence should be addressed to Melanie K. Tallent, Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102. Email: tallent{at}drexel.edu

The K⁺ M-current (I_M, Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin (SST), which has antiepileptic properties, augments I_M in hippocampal CA1 pyramidal neurons. We used SST receptor knock-out mice and subtype-selective ligands to investigate the receptor subtype that couples to I_M and mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant, SST₂, SST₃, and SST₄ receptor knock-out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild-type mice. However, the most robust differences were observed in the SST₄ knock-outs. When seizures were induced by systemic injection of kainate, only SST₄ knock-outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype-selective SST agonists on electrophysiological parameters in hippocampal slices of wild-type and receptor knock-out mice. SST₂ and SST₄ appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increased I_M in CA1 pyramidal neurons of wild-type and SST₂ knock-out mice, but not SST₄ knock-out mice. Using M-channel blockers, we found that SST₄ coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of I_M that is important in controlling seizure activity. SST₄ receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.

Key words: somatostatin; Kv7 channels; KCNQ; epilepsy; knock-out mice; electrophysiology

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Received Oct. 15, 2007; revised Feb. 18, 2008; accepted Feb. 22, 2008.

Correspondence should be addressed to Melanie K. Tallent, Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102. Email: tallent{at}drexel.edu

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